Role of xanthine oxidase in ethanol-induced lipid peroxidation in rats.
To investigate a possible role of free radical production by xanthine oxidase in the pathogenesis of ethanol-induced hepatic lipid peroxidation, chow-fed rats were given ethanol (5 g/kg) and placed at 32 degrees C for 6 h, which resulted in increased hepatic malondialdehyde levels. Pretreatment with allopurinol in amounts that effectively inhibited xanthine metabolism also significantly decreased ethanol-induced lipid peroxidation, suggesting participation of free radicals produced by xanthine oxidase in the peroxidative process. Both acetaldehyde and purine can serve as substrates for xanthine oxidase. Pretreatment with cyanamide increased hepatic acetaldehyde levels 5-fold, yet this was associated with a decrease in lipid peroxidation, indicating that acetaldehyde is not the xanthine oxidase substrate involved. By contrast, ethanol increased hepatic contents of hypoxanthine and xanthine and enhanced urinary output of allantoin (a final product of xanthine metabolism), incriminating increased metabolism of purines. Ethanol administration also enhanced hepatic nicotinamide adenine dinucleotide (reduced form). A corresponding rise of nicotinamide adenine dinucleotide (reduced form) in vitro inhibited xanthine dehydrogenase activity by 60%-76%. Increased purine degradation, possibly associated with a shift from the dehydrogenase to the xanthine oxidase pathway (secondary to nicotinamide adenine dinucleotide [reduced form]-mediated inhibition of xanthine dehydrogenase activity) is proposed as a possible mechanism for ethanol-stimulated free radical production. Because allopurinol attenuates the associated lipid peroxidation, this agent might be considered for possible therapeutic use in alcohol-induced liver damage.
Kato
S
S
Alcohol Research and Treatment Center, Veterans Administration Medical Center, Bronx, New York.
Kawase
T
T
Alderman
J
J
Inatomi
N
N
Lieber
C S
CS
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D003484:Cyanamide / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005609:Free Radicals; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011292:Premedication; D051381:Rats; D011919:Rats, Inbred Strains; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000502:physiology*
D005609:Free Radicals; D000431:Ethanol; D003484:Cyanamide; D000493:Allopurinol; D014969:Xanthine Oxidase